Methods of treating migraine

ABSTRACT

The present disclosure provides methods for the treatment of migraine by the administration of atogepant or a pharmaceutically acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalApplication No. 63/261,731, filed Sep. 27, 2021; U.S. ProvisionalApplication No. 63/261,782, filed Sep. 28, 2021; U.S. ProvisionalApplication No. 63/261,783, filed Sep. 28, 2021; U.S. ProvisionalApplication No. 63/336,843, filed Apr. 29, 2022; and U.S. ProvisionalApplication No. 63/395,134, filed Aug. 4, 2022. The entire contents ofeach of these applications is incorporated herein by reference in itsentirety.

FIELD

The present disclosure is related to medicaments and methods fortreating migraine.

BACKGROUND

Migraine is a highly prevalent, severe, and disabling neurologicalcondition with a significant unmet need for effective treatments.(Holland, P. R. & Goadsby, P. J. Neurotherapeutics (2018). Migraineaffects over 1 billion people worldwide, and it was reported as thesecond leading cause of disability in the 2016 Global Burden of Diseasestudy. See GBD 2019 Diseases and Injuries Collaborators. Global Burdenof 369 diseases and injuries in 204 countries and territories,1990-2019: a systemic analysis for the Global Burden of Disease Study2019, Lancet 2020; 396:1204-22.

When attacks are frequent or disabling, prevention becomes a focus ofmigraine treatment. Current preventive treatments for migraine includeoral medications, such as valproic acid, flunarizine, topiramate, andpropranolol, as well as injectable treatments, such as monoclonalantibodies targeting calcitonin gene-related peptide (CGRP).

There remains a need for targeted methodologies and dosing regimens touse oral CGRP treatments to prophylactically treat migraines.

SUMMARY

In embodiments, the present disclosure provides methods for thepreventive treatment of migraine in a patient, wherein the patient isundergoing concurrent treatment with a strong CYP3A4 inhibitor, themethod comprising administering atogepant 10 mg once daily.

In embodiments, the present disclosure provides methods for thepreventive treatment of migraine in a patient, wherein the patient isundergoing concurrent treatment with a moderate or strong CYP3A4inducer, the method comprising administering 30 mg or 60 mg atogepantonce daily.

In embodiments, the present disclosure provides methods for thepreventive treatment of migraine in a patient, wherein the patient isundergoing concurrent treatment with an OATP inhibitor, the methodcomprising administering 10 mg or 30 mg atogepant once daily.

In embodiments, the present disclosure provides methods for thepreventive treatment of migraine in a patient, wherein the patient hassevere renal impairment or end-stage renal disease (CLcr<30 mL/min), themethod comprising administering 10 mg atogepant once daily.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the mean plasma atogepant concentration-time profilesfollowing administration of atogepant alone or in combination withsingle-dose rifampin to Fasted Healthy Participants.

FIG. 2 shows the mean plasma atogepant concentration-time profilesfollowing oral administration of atogepant alone or in combination withmultiple-dose rifampin to Fasted Healthy Participants.

FIG. 3 shows the mean plasma concentrations of atogepant after theadministration of 60 mg either alone or in the presence of steady stateitraconazole, a strong CYP3A4 inhibitor.

FIG. 4 shows a semilogarithmic plot of the mean plasma concentrations ofatogepant 60 mg either alone or in the presence of steady stateitraconazole.

FIG. 5A shows the mean plasma atogepant concentration-time profiles(linear scale) following single dose oral administration of 60 mgatogepant in participants with mild, moderate, or severe hepaticimpairment and in participants with normal hepatic function (N=8 in eachgroup). FIG. 5B shows a corresponding semi-logarithmic plot. FIG. 5Apresents a full profile up to 72 hours, while 5B shows a truncatedprofile up to 8 hours.

FIG. 6 shows the mean change from baseline in monthly migraine days inStudy 1 (NCT03777059).

FIG. 7 shows the distribution of change from baseline in mean monthlymigraine days (MMD) across the 12-week treatment period, in 2-dayincrements, by treatment group in Study 1.

FIG. 8 shows the mean change from baseline in MMD in Study 2(NCT02848326).

FIG. 9 shows the distribution of change from baseline in mean MMD acrossthe 12-week treatment period, in 2-day increments, by treatment group inStudy 2. A treatment benefit over placebo for all doses of atogepant isseen across a range of mean changes from baseline in MMD.

FIG. 10 provides the mean concentration-time profiles for plasmaatogepant after single dose administration of a 1×60 mg atogepant IRtablet formulation under fed conditions and under fasted conditions(linear scale±SD, with semilogarithmic scale insert).

FIG. 11 provides boxplots of AUC_(0-t) and AUC_(0-inf) after single doseadministration of a 1×60 mg atogepant IR tablet formulation under fedconditions and under fasted conditions.

FIG. 12 provides a boxplot of C_(max) after single dose administrationof a 1×60 mg atogepant IR tablet formulation under fed conditions andunder fasted conditions.

FIG. 13 provides the study design and dosing schedule for an open-label,single-center, multiple-dose 2-cohort, phase 1 trial to evaluate thepotential DDI between atogepant and topiramate in healthy adultparticipants.

FIG. 14 shows the mean steady state plasma concentrations of atogepantfollowing administration alone and in combination with topiramate inlinear and semi-logarithmic scale.

FIG. 15 shows mean (±SD) steady state plasma atogepant concentrationswhen administered alone and in combination with topiramate, in linearand semi-logarithmic scale.

DETAILED DESCRIPTION

The present disclosure provides methods for treating migraine in apatient in need thereof. In embodiments, the present disclosure providesmethods for the prophylactic treatment of patients suffering frommigraine. In embodiments, the present disclosure provides methods forthe preventive treatment of episodic migraine. In embodiments, thepresent disclosure provides methods for the treatment of migraine, suchas the preventive treatment of episodic migraine, comprisingadministering a prophylactically effective amount of atogepant or apharmaceutically acceptable salt thereof. The chemical name of atogepantis(3′S)-N-[(3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxamide,and it has the following structural formula:

Atogepant is a small molecule calcitonin gene-related peptide (CGRP)receptor antagonist which may be administered orally as, for example, atablet. In embodiments, atogepant is administered for the preventivetreatment of migraine, such as episodic migraine. In embodiments,atogepant is administered for the preventive treatment of episodicmigraine at a once daily dose of 10 mg, 30 mg, or 60 mg.

Following oral administration, atogepant is absorbed with peak plasmaconcentrations at approximately 1 to 2 hours. Following once dailydosing, atogepant displays dose-proportional pharmacokinetics up to 170mg, with no accumulation.

When atogepant is administered with a high-fat meal, the food effect wasnot significant (AUC and C_(max) were reduced by approximately 18% and22%, respectively, with no effect on median time to maximum atogepantplasma concentration). In embodiments, atogepant may be administeredwithout regard to food.

Plasma protein binding of atogepant was not concentration-dependent inthe range of 0.1 to 10 μM; the unbound fraction of atogepant wasapproximately 4.7% in human plasma. The mean apparent volumedistribution of atogepant (Vz/F) after oral administration isapproximately 282 L.

Atogepant is eliminated mainly through metabolism, primarily by CYP3A4.The parent compound (atogepant) and a glucuronide conjugate metabolite(M23) were the most prevalent circulating components in human plasma.The elimination half-life of atogepant is approximately 11 hours. Themean apparent oral clearance (CL/F) of atogepant is approximately 19L/hr. Following a single oral dose of 50 mg ¹⁴C-atogepant to healthymale subjects, 42% and 5% of the dose was recovered as unchangedatogepant in feces and urine, respectively.

In vitro, atogepant is not an inhibitor for CYPs 3A4, 1A2, 2B6, 2C8,2C9, 2C19, or 2D6 at clinically relevant concentrations. Atogepant doesnot inhibit MAO-A or UGT1A1 at clinically relevant concentrations.Atogepant is not an inducer of CYP1A2, CYP2B6, or CYP3A4 at clinicallyrelevant concentrations.

Atogepant is a substrate of P-gp, BCRP, OATP1B1, OATP1B3, and OAT1.Atogepant is not an inhibitor of P-gp, BCRP, OAT1, OAT3, NTCP, BSEP,MRP3, or MRP4 at clinically relevant concentrations. Atogepant is a weakinhibitor of OATP1B1, OATP1B3, OCT1, and MATE 1.

The terms “concurrent”/“concurrently” or “concomitant”/“concomitantly”both include in their meaning (1) simultaneously in time (e.g., at thesame time) and (2) at different times but within the course of a commontreatment schedule.

Coadministration of Atogepant and a CYP3A4 Inhibitor

Coadministration of atogepant with itraconazole, a strong CYP3A4inhibitor, resulted in a significant increase in exposure of atogepantin healthy subjects. Co-administration of atogepant with itraconazoleresulted in a clinically significant increase (Cmax by 2.15-fold and AUCby 5.5-fold) in the exposure of atogepant in healthy subjects.Population pharmacokinetic modeling suggested co-administration ofatogepant with moderate CYP3A4 inhibitors (e.g., cyclosporine,ciprofloxacin, fluconazole, fluvoxamine, grapefruit juice) or weakCYP3A4 inhibitors (e.g., cimetidine, esomeprazole) increase atogepantAUC by 1.7- and 1.1-fold, respectively. The changes in atogepantexposure when coadministered with weak or moderate CYP3A4 inhibitors arenot expected to be clinically significant.

In embodiments, the present disclosure provides methods for thepreventive treatment of migraine, such as the preventive treatment ofepisodic migraine, when atogepant is used concomitantly with a strongCYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin).

In embodiments, the present disclosure provides a method for thepreventive treatment of migraine (such as the preventive treatment ofepisodic migraine) in a patient undergoing concurrent treatment with astrong CYP3A4 inhibitor, the method comprising administering 10 mgatogepant once daily. In embodiments, the CYP3A4 inhibitor isketoconazole, itraconazole, or clarithromycin. In embodiments,co-administration of 10 mg atogepant and the strong CYP3A4 inhibitorresults in an increase in atogepant Cmax of less than 2.15-fold relativeto administration of atogepant alone. In embodiments, coadministrationof 10 mg atogepant and the strong CYP3A4 inhibitor (e.g., itraconazole)results in an increase in atogepant AUC of less than or equal to5.5-fold relative to administration of atogepant alone. In embodiments,atogepant is administered with or without food. In embodiments, theCYP3A4 inhibitor may be administered before, concomitantly with, orafter atogepant is administered.

In embodiments, the present disclosure provides a method for thepreventive treatment of migraine (such as the preventive treatment ofepisodic migraine) in a patient, the method comprising administering 10mg or 30 mg or 60 mg of atogepant once daily, wherein if the patientbegins concurrent treatment with a strong CYP3A4 inhibitor, the dose ofatogepant is adjusted to 10 mg once daily. In embodiments, the CYP3A4inhibitor may be administered before, concomitantly with, or afteratogepant is administered.

In embodiments, the present disclosure provides a method for thepreventive treatment of migraine (such as the preventive treatment ofepisodic migraine) in a patient undergoing concurrent treatment with amoderate CYP3A4 inhibitor, the method comprising administering 10 mg, 30mg, or 60 mg atogepant once daily. In embodiments, the moderate CYP3A4inhibitor is cyclosporine, ciprofloxacin, fluconazole, fluvoxamine, andgrapefruit juice. In embodiments, coadministration of atogepant and themoderate CYP3A4 inhibitor increases atogepant AUC by about 1.7-fold orless, relative to administration of atogepant alone. In embodiments,atogepant is administered orally with or without food. In embodiments,the CYP3A4 inhibitor may be administered before, concomitantly with, orafter atogepant is administered.

In embodiments, the present disclosure provides a method for thepreventive treatment of migraine (such as the preventive treatment ofepisodic migraine) in a patient undergoing concurrent treatment with aweak CYP3A4 inhibitor, the method comprising administering 10 mg, 30 mg,or 60 mg atogepant. In embodiments, the mild CYP3A4 inhibitor iscimetidine or esomeprazole. In embodiments, coadministration of 10 mg,30 mg, or 60 mg atogepant and the weak CYP3A4 inhibitor increases AUC byabout 1.1-fold or less, relative to administration of atogepant alone.In embodiments, atogepant is administered orally with or without food.In embodiments, the CYP3A4 inhibitor may be administered before,concomitantly with, or after atogepant is administered.

Coadministration of Atogepant and a CYP3A4 Inducer

Co-administration of atogepant with rifampin, a strong CYP3A4 inducer,decreased atogepant AUC by 60% and Cmax by 30% in healthy subjects.Moderate inducers of CYP3A4 can decrease atogepant exposure.

In embodiments, the present disclosure provides a method for thepreventive treatment of migraine (such as the preventive treatment ofepisodic migraine) in a patient undergoing concurrent treatment with astrong or moderate CYP3A4 inducer, the method comprising administering30 mg or 60 mg atogepant. In embodiments, the strong CYP3A4 inducer isrifampin, carbamazepine, phenytoin, St. John's wort, efavirenz, oretravirine. In embodiments, atogepant is administered with the CYP3A4inducer has reached a steady state. In embodiments, the AUC of atogepantis decreased by less than about 60% when 30 mg or 60 mg atogepant isadministered with the moderate or strong CYP3A4 inducer relative toadministration of atogepant alone. In embodiments, the atogepant Cmax isdecreased by less than about 30% when co-administered with the moderateor strong CYP3A4 inducer relative to administration of atogepant alone.In embodiments, atogepant is administered orally with or without food.In embodiments, the CYP3A4 inducer may be administered before,concomitantly with, or after atogepant is administered.

In embodiments, the present disclosure provides a method for thepreventive treatment of migraine (such as the preventive treatment ofepisodic migraine) in a patient undergoing concurrent treatment with aweak CYP3A4 inducer, the method comprising administering 10 mg or 30 mgor 60 mg atogepant. In embodiments, atogepant is administered orallywith or without food. In embodiments, the CYP3A4 inducer may beadministered before, concomitantly with, or after atogepant isadministered.

For example, in embodiments, the present disclosure provides a methodfor the preventive treatment of migraine (such as the preventivetreatment of episodic migraine) in a patient undergoing concurrenttreatment with topiramate, a mild CYP3A4 inducer. Topiramate is acommonly prescribed oral antiepileptic approved by the FDA and theEuropean Medicines Agency (EMA) for the preventive treatment of migraine(100 mg/day administered in 2 divided doses) in individuals of at least12 years of age. Topiramate blocks voltage-dependent sodium channels,inhibits carbonic anhydrase, blocksα-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, and enhancesgamma-aminobutyric acid-mediated inhibition. Topiramate is a mildinducer of CYP3A4 activity with a long elimination half-life ofapproximately 21 hours, whereas atogepant is extensively metabolizedpredominantly by CYP3A4 with a minor contribution from CYP2D6, and hasan elimination half-life of approximately 11 hours.

In embodiments, the present disclosure provides a method for thetreatment of migraine, in particular the preventive treatment ofmigraine (such as the preventive treatment of episodic migraine), themethod comprising administering topiramate and atogepant. Inembodiments, atogepant is administered with or without food. Inembodiments, topiramate is administered before, concomitantly with, orafter administration of atogepant. In embodiments, atogepant isadministered at a dose of 10 mg or 30 mg or 60 mg once daily. Inembodiments, topiramate is administered at a dose from about 1 to about300 mg, such as from about 25 mg to about 200 mg. In embodiments,topiramate is administered at a dose of about 25 mg, or about 50 mg, orabout 100 mg, or about 200 mg. In embodiments, topiramate isadministered at a dose of about 100 mg/day. In embodiments, topiramateis administered in two divided doses. In embodiments, topiramate isadministered at a dose of 25 mg twice daily (e.g., morning and evening),or 25 mg in the morning and 50 mg in the evening, or 50 mg in themorning and 25 mg in the evening, or 50 mg twice daily (e.g., morningand evening). In embodiments, coadministration of topiramate andatogepant reduces atogepant AUC_(0-tau,ss) by about 25% and reducesatogepant C_(max,ss) by about 24%.

Coadministration of Atogepant and an OATP Inhibitor

Co-administration of atogepant with single dose rifampin, an OATPinhibitor, increased atogepant AUC by 2.85-fold and Cmax by 2.23-fold inhealthy subjects.

In embodiments, the present disclosure provides a method for thepreventive treatment of migraine (such as the preventive treatment ofepisodic migraine) in a patient undergoing concurrent treatment with anOATP inhibitor, the method comprising administering 10 mg or 30 mgatogepant once daily. In embodiments, coadministration of 10 mg or 30 mgatogepant with an OATP inhibitor results in an increase in atogepant AUCof about 2.8-fold or less relative to administration of atogepant alone.In embodiments, coadministration of 10 mg or 30 mg atogepant with anOATP inhibitor results in an increase in atogepant Cmax of about2.2-fold or less relative to administration of atogepant alone. Inembodiments, atogepant is administered orally with or without food. Inembodiments, the OATP inhibitor may be administered before,concomitantly with, or after atogepant is administered.

Coadministration of Atogepant and Rifampin

As discussed above, atogepant is metabolized by CYP3A4 with a minorcontribution from CYP2D6, and is also a substrate of several membranetransporters, including P-gp and OATP1B1. Rifampin is an inducer of bothCYP3A4 and P-gp, while also being an inhibitor of OATP in-vitro.

The present inventors have determined that, when a single dose ofatogepant 60 mg is coadministered with a single dose of rifampin 600 mg,atogepant AUC₀₋₂₄ and C_(max) were 2.85-fold and 2.23-fold higher,respectively, than administration of atogepant alone. These increases inatogepant C_(max) and AUC could be clinically significant. Without beingbound to any particular theory, the increase in atogepant C_(max) andAUC₀₋₂₄ after co-administration of single-dose rifampin represents theinhibition of the influx transporter OATP in the liver by rifampin,resulting in a reduced availability of atogepant to the hepatocytes formetabolism, thus leading to higher atogepant levels in plasma.

The present inventors have further determined that, when a single doseof atogepant 60 mg is coadministered with multiple-dose of rifampin 600mg, atogepant AUC_(0-inf) and AUC_(0-t) were reduced by 61% and 60%,respectively, and C_(max) was reduced by 30%, relative to administrationof atogepant alone. Without being bound to any particular theory, thedecrease in atogepant C_(max) and AUC after coadministration withmultiple-dose rifampin represents the induction of P-gp and CYP3A4,resulting in a decreased rate of absorption and increased rate ofmetabolism of atogepant, respectively. Systemic clearance was increasedfrom 22.8 L/h following atogepant administration alone to 58.3 L/hfollowing atogepant administration in the presence of multiple-doserifampin. Without being bound to any particular theory, the reduction inT_(1/2) represents the induction of CYP3A4 by rifampin, leading to anincreased elimination rate of plasma atogepant and an increase in theslope of the terminal elimination phase. Although rifampin is likelystill inhibiting OATP after five days of rifampin dosing, overall theinductive effects on CYP3A4 and P-gp outweigh the inhibition of OATP,resulting in a decrease of atogepant exposure with multiple-doserifampin.

The present disclosure provides a method of preventing migraine in apatient, the method comprising administering 10 mg, 30 mg, or 60 mgatogepant once daily, wherein if the patient is coadministered multipledoses of rifampin, the patient is administered 30 mg or 60 mg atogepantonce daily. In embodiments, 30 mg or 60 mg atogepant once daily isadministered when the patient is administered multiple doses ofrifampin, despite an increase in atogepant AUC₀₋₂₄ and C_(max) of2.85-fold and 2.23-fold, respectively, if atogepant is administered witha single dose of rifampin. In embodiments, coadministration of 30 mg or60 mg atogepant once daily with multiple doses of rifampin results in adecrease in atogepant AUC of about 60% or less relative toadministration of atogepant alone. In embodiments, coadministration of30 mg or 60 mg atogepant once daily with multiple doses of rifampinresults in a decrease in atogepant Cmax of about 30% relative toadministration of atogepant alone. In embodiments, atogepant isadministered orally with or without food. In embodiments, rifampin maybe administered before, concomitantly with, or after atogepant isadministered.

In embodiments, the present disclosure provides a method of preventingmigraine in a patient undergoing concurrent treatment with a drug thatis a strong inducer of CYP3A4 and an inhibitor of OATP, the methodcomprising administering 30 mg or 60 mg atogepant once daily. Inembodiments, coadministration of 30 mg or 60 mg atogepant once dailywith multiple doses of the CYP3A4 inducer/OATP inhibitor results in adecrease in atogepant AUC of about 60% or less relative toadministration of atogepant alone. In embodiments, coadministration of30 mg or 60 mg atogepant once daily with multiple doses of the CYP3A4inducer/OATP inhibitor results in a decrease in atogepant Cmax of about30% or less relative to administration of atogepant alone. Inembodiments, atogepant is administered orally with or without food.

Methods for the Preventive Treatment of Migraine in Patients with RenalImpairment

The renal route of elimination plays a minor role in the clearance ofatogepant. Using a population pharmacokinetic analysis based onestimated creatinine clearance (CLcr), the present inventors determinedthat there is no significant difference in the pharmacokinetics ofatogepant in patients with mild or moderate renal impairment (CLcr 30-89mL/min) relative to those with normal renal function (CLcr>90 mL/min).

In embodiments, the present disclosure provides a method for thepreventive treatment of migraine in patients having mild renalimpairment (glomelular filtration rate [GFR] 60-90 mL/min), the methodcomprising administering 10 mg or 30 mg or 60 mg atogepant once daily.In embodiments, atogepant is taken orally with or without food. Inembodiments, administration of 10 mg or 30 mg or 60 mg atogepant oncedaily to a patient having mild renal impairment results in an increasein atogepant C_(max) of less than about 20%, such as less than about15%, or less than about 13%, relative to patients with normal renalfunction. In embodiments, administration of 10 mg or 30 mg or 60 mgatogepant once daily to a patient having mild renal impairments resultsin an increase in atogepant 24-hour AUC of less than about 30%, such asless than about 25%, or less than about 20%.

In embodiments, the present disclosure provides a method for thepreventive treatment of migraine in patients having moderate renalimpairment (GFR 30-60 mL/min), the method comprising administering 10 mgor 30 mg or 60 mg atogepant once daily. In embodiments, atogepant istaken orally with or without food. In embodiments, administration of 10mg or 30 mg or 60 mg atogepant once daily to a patient having moderaterenal impairment results in an increase of atogepant C_(max) by lessthan about 20%, such as less than about 15%, or less than about 13%,relative to patients with normal renal function. In embodiments,administration of 10 mg or 30 mg or 60 mg atogepant results in anincrease in atogepant 24-hour AUC of less than about 50%, or less thanabout 45%, relative to patients with normal renal function.

In embodiments, atogepant dose adjustment may be required in patientswith severe renal impairment (CLcr 15-29 mL/min) or end stage renaldisease (CLcr<30 mL/min). In embodiments, the present disclosureprovides a method for the preventive treatment of migraine in patientshaving severe renal impairment, the method comprising administering 10mg atogepant once daily to a patient having severe renal impairment(CLcr 15-29 mL/min). In embodiments, the present disclosure provides amethod for the preventive treatment of migraine in patients having endstage renal disease (CLcr<30 mL/min), the method comprisingadministering 10 mg atogepant once daily to a patient having end stagerenal disease. In embodiments, atogepant is taken orally with or withoutfood.

Methods for the Preventive Treatment of Migraine in Patients HavingHepatic Impairment

In embodiments, the present disclosure provides methods of safelyadministering atogepant to patients having mild or moderate hepaticimpairment for the preventive treatment of migraine, such as episodicmigraine. In embodiments, the hepatic impairment is pre-existing.

The term “hepatic impairment” refers to scoring based on the Child-PughScore of A, B, and C. In embodiments, mild hepatic impairment refers toChild-Pugh Class A; moderate hepatic impairment refers to Child-PughClass B; and severe hepatic impairment refers to Child-Pugh Class C.

In patients with pre-existing mild (Child-Pugh Class A), moderate(Child-Pugh Class B), or severe hepatic impairment (Child-Pugh Class C),it was determined that the total atogepant exposure was increased by24%, 15%, and 38%, respectively.

In embodiments, the present disclosure provides methods for thepreventive treatment of migraine in patients having mild or moderatehepatic impairment, the method comprising administering atogepant 10 mgor 30 mg or 60 mg once daily. In embodiments, atogepant is administeredwith or without food.

In embodiments, the present disclosure provides methods for thepreventive treatment of migraine in patients having hepatic impairment,the method comprising administering 10 mg or 30 mg or 60 mg once daily,wherein if the patient develops severe hepatic impairment (Child-PughClass C), atogepant treatment is discontinued.

Transaminase Elevations in Atogepant-Treated Patients vs. Placebo

In embodiments, the present disclosure provides methods for thepreventive treatment of migraine, such as the preventive treatment ofepisodic migraine, comprising administering atogepant, wherein thetreatment with atogepant does not significantly affect the level ofliver enzymes, such as alanine aminotransferase (ALT) or aspartateaminotransferase (AST).

In embodiments, the present disclosure provides a method for thepreventive treatment of migraine in a population of patients, the methodcomprising administering 10 mg or 30 mg or 60 mg atogepant once daily tothe population of patients, wherein the rate of transaminase elevationsover 3 times the upper limit of normal (ULN) in the population ofpatients is lower than a rate of transaminase elevations over 3 timesthe upper limit of normal in a population of patients treated withplacebo. In embodiments, atogepant is administered to the population ofpatients for at least 3 weeks, or at least about 6 weeks, or at leastabout 9 weeks, or at least about 12 weeks, or at least about 16 weeks,or at least about 20 weeks, or at least about 24 weeks, or at leastabout 52 weeks, and the rate of transaminase elevations over 3 times theupper limit of normal (ULN) in the population of patients is lower thana rate of transaminase elevations over 3 times the upper limit of normalin a population of patients treated with placebo.

Food Effect

As previously mentioned, the present disclosure provides methods for thepreventive treatment of migraine, such as the preventive treatment ofepisodic migraine, by administering 10 mg or 30 mg or 60 mg atogepantonce daily to a patient in need thereof. In embodiments, atogepant maybe taken without regard to whether a patient has eaten, sometimesreferred to as “without regard to meals”, “can be taken with or withoutfood”, “no food effect”, or similar phrases.

More particularly, the inventors of the present disclosure havedetermined that, while a statistically significant food effect isdemonstrated on the pharmacokinetics of atogepant, this food effect isnot clinically relevant, and a patient can take atogepant with orwithout food. Accordingly, atogepant can advantageously be taken at anytime regardless of whether the patient has recently eaten.

Generally, a fasted state refers to the fact that a patient has noteaten for a given amount of time before taking a dose of medication, aswell as not eating for a given amount of time after taking the dosageform. These time periods before and after dosing can range between, forexample, 2 hours to 24 hours. A fed state generally refers to the factthat a patient has eaten within a given time period of taking aparticular medication. The time period is variable but may constitute,for example, a meal just before, during, or just after taking themedication, such as within about an hour of dosing. The quantity of foodeaten that will qualify as a fed state is also variable but generallycan comprise between about 500 to about 1500 kcal of food.

EXAMPLE 1

A single-center, Phase 1, open-label, two treatment, two period, singlesequence, non-randomized crossover interaction study between atogepantand rifampin in 32 healthy, adult male or female participants betweenthe ages of 18 and 45 years of age, inclusive, was conducted.

The study consisted of a Screening Visit, two study periods, anend-of-treatment (EOT) visit, and a follow-up visit. During StudyPeriods 1 and 2, participants received a total of three treatments withtwo atogepant washout periods, as described in Table 1.

TABLE 1 Study Design Screening (Days −14 to −1) Was to be conductedwithin 14 days before Day 1 Period 1 Participants were to stay at thestudy center overnight (Days −1 on Days −1, 1, and 2 and discharged fromthe study to 5) center on Day 3. In this period, participants received:Treatment A: A single 60 mg atogepant dose on Day 1 No procedures wereperformed on Days 4 and 5 and participants were not required to returnto the study center. Days 4 and 5 were a continuation of the first 6-daywashout period for atogepant following the first single dose on Day 1.Period 2 Participants were to stay at the study center overnight (Days 6to 14) on Days 6 and 7 and were discharged from the study center on Day8. Participants returned for outpatient visits on Days 9 and 10. On Day11, participants returned to the study center to stay overnight on Days11, 12, and 13, and were discharged from the study center on Day 14. Inthis period, participants received: Treatment B1: Co-administration of60 mg atogepant and 600 mg rifampin on Day 7 followed by 600 mg rifampinalone, once daily, on Days 8, 9, 10, and 11. Participants receivedrifampin on an outpatient basis on Days 9 and 10. Treatment B2:Co-administration of 60 mg atogepant and 600 mg rifampin on Day 12followed by 600 mg rifampin alone on Day 13. The second atogepantwashout period was 5 days between Treatment B1 and B2 (from Day 7 to Day12). EOT Visit Was conducted on Day 14, within 7 days after Day 14 on anoutpatient basis, or at the time of early termination. Follow-Up Wasconducted on an outpatient basis on Day 43 (±2 Visit days) or 30 (±2days) days after the last dose of study treatment if a participantdiscontinued dosing early.

Study assessments included blood sample collections for evaluation ofatogepant plasma PK and plasma trough concentrations of rifampin. Inaddition, the safety and tolerability of atogepant when given alone andin combination with rifampin was monitored throughout the study byclinical assessment of AEs and by measurement of vital signs, physicalexaminations, 12-lead ECGs, and clinical laboratory tests (hematology,serum chemistry, and urinalysis).

Not including screening, the anticipated duration of study participationwas a maximum of 46 days (Day −1 through the follow-up visit on Day 43(±2 days)).

Inclusion criteria included healthy male or female participants, 18 to45 years of age with a BMI ≥18 kg/m² and ≤30 kg/m². Participants werenon-smokers and non-users of nicotine-containing products and hadnegative urine drug screens.

Participants who had a clinically significant disease state, in theopinion of the examining investigator or designee, in any body system orwho had any clinical condition or previous surgery that could haveaffected the absorption, distribution, biotransformation, or excretionof atogepant or rifampin were excluded from the study. Participants alsocould not have had a history of alcohol or other substance abuse withinthe previous 5 years.

The study treatments that were administered (atogepant and rifampin) andthe dosing regimens (Treatment A, Treatment B 1, and Treatment B2) aredescribed below:

-   -   Treatment A: A single dose of 60 mg atogepant (1×60 mg tablet)        on Day 1    -   Treatment B1: Co-administration of 60 mg atogepant and 600 mg        rifampin (2×300 mg capsules) on Day 7 and 600 mg rifampin alone,        once daily, on Days 8, 9, 10, and 11    -   Treatment B2: Co-administration of 60 mg atogepant and 600 mg        rifampin on Day 12 and 600 mg rifampin alone on Day 13.

The atogepant washout period was 6 days between Treatments A and B1 and5 days between Treatments B1 and B2.

There were three analysis populations used for analysis of data fromthis study:

-   -   The Safety Population consisted of all participants who received        at least one dose of study treatment.    -   The PK Population for atogepant consisted of all participants        who had evaluable PK parameters for atogepant following all        treatments (Treatments A, B1, and B2).    -   The PK Population for rifampin consisted of all participants who        had measurable plasma concentrations for rifampin.

The mean age of participants in the safety population was 31.3 years.The proportion of female participants was higher than that for maleparticipants (59.4% versus 40.6%). White and black or African Americanparticipants accounted for 50.0% and 46.9% of the safety population,respectively; 1 (3.1%) was Asian. Nineteen (59.4%) participants werenon-Hispanic and 13 (40.6%) were of Hispanic ethnicity. The mean BMI ofthe safety population was 25.67 kg/m².

When atogepant was to be administered alone or in combination withrifampin, participants were required to undergo a 10-hour overnight fastprior to dosing (beginning on Days −1, 6, and 11) and were required tomaintain the fast for an additional 4 hours following doseadministration (on Days 1, 7, and 12).

When rifampin was to be administered alone (on Days 8, 9, 10, 11, and13), no food should have been administered for 1 hour before and 1 hourafter dosing.

All treatments were administered with approximately 240 mL of water;water was provided for participants at other times as desired, exceptfor 1 hour before and after dose administration.

Relative to the time that atogepant was administered, blood samples foratogepant plasma PK were to be collected at the following times:

-   -   Days 1 and 12: 0 hour (predose) and at 0.5, 1, 1.5, 2, 3, 4, 6,        8, 12, 16, 24, 36, and 48 hours post dose.    -   Day 7: 0 hour (predose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12,        16, and 24 hours postdose

Blood samples for plasma trough concentrations of rifampin were to becollected at:

-   -   Days 11 and 12: 0 hour (predose) prior to rifampin        administration

The mean plasma atogepant concentration-time profiles are presented inFIGS. 1 and 2 . In particular, FIG. 1 illustrates the mean plasmaatogepant concentration-time profiles following administration ofatogepant alone (Reference, Treatment A) or in combination withsingle-dose rifampin (Test, Treatment B1) to Fasted HealthyParticipants. FIG. 2 provides the mean plasma atogepantconcentration-time profiles following oral administration of atogepantalone (Reference, Treatment A) or in combination with multiple-doserifampin (Test, Treatment B2) to Fasted Healthy Participants.

A summary of the mean PK parameters for atogepant when administeredalone or in combination with rifampin is presented in Table 2.

TABLE 2 Mean (SD) Atogepant Pharmacokinetic Parameters followingAtogepant 60 mg Alone on Day 1 (Treatment A), or in Combination with 600mg Rifampin on Day 7 Followed by 600 mg Rifampin Alone, Once Daily, onDays 8, 9, 10, and 11 (Treatment B1) or in Combination with 600 mgRifampin on Day 12 Followed by 600 mg Rifampin Alone on Day 13(Treatment B2) (PK Population) Treatment A Treatment B1 Treatment B2 PKParameter N = 31 N = 31 N = 31 T_(max) (h)^(a) 1.50 (0.500-2.00) 2.00(1.00-4.00) 1.50 (1.00-3.00) C_(max) (ng/mL) 711 (328) 1550 (624) 487(192) AUC₀₋₂₄ (ng · h/mL) 2870 (1060) 8130 (3260) — AUC_(0-t) (ng ·h/mL) 2960 (1100) — 1180 (358) AUC_(0-∞) (ng · h/mL) 3000 (1100) —1130^(b) (332) t_(1/2) (h) 11.4 (5.55) — 2.39^(b) (1.09) V_(z)/F (L) 390(271) — 197^(b) (105) CL/F (L/h) 22.8 (8.44) — 58.3^(b) (21.8) λz (1/h)0.0778 (0.411) — 0.325^(b) (0.0833) ^(a)Median (Range) ^(b)N = 28

The median T_(max) value for atogepant as similar following atogepantadministered alone compared with in combination with single-dose orafter multiple dose rifampin (Treatments B1 and B2, respectively). Themean apparent T_(1/2) of atogepant was reduced by approximately 9 hours(11.4 hours vs. 2.39 hours) following atogepant administered alonecompared with in combination with multiple dose rifampin.

Treatment B1/Treatment A: In the comparison of a single dose ofatogepant 60 mg coadministered with single dose of rifampin 600 mg(Test) versus a single dose of atogepant 60 mg administered alone(Reference), Atogepant AUC₀₋₂₄ and C_(max) were 2.85-fold and 2.23-foldhigher, respectively. These increases in atogepant C_(max) and AUC couldbe clinically significant.

Treatment B2/Treatment A: In the comparison of a single dose ofatogepant 60 mg coadministered with multiple-dose of rifampin 600 mg(Test) versus a single dose of atogepant 60 mg atogepant administeredalone (reference), atogepant AUC_(0-∞) and AUC_(0-t) were reduced by 61%and 60%, respectively, and C_(max) was reduced by 30%. These decreasesin atogepant C_(max) and AUC could be clinically significant.

TABLE 3 Summary of Statistical Analysis Results of Plasma AtogepantPharmacokinetic Parameters Following Oral Administration of Single Dose600 mg Rifampin in Combination with 60 mg Atogepant (Treatment B1, Test)in Comparison to 60 mg Atogepant Administered Alone (Treatment A,Reference) in Healthy Adult Participants (N = 31, PK population) Ratioof Geometric 90% Lower 90% Upper PK Geometric LSM Means (%) ConfidenceConfidence Parameter Test Reference Test/Ref Interval Interval AUC₀₋₂₄7631.86 2679.39 284.84 260.29 311.69 (ng · h/mL) C_(max) (ng/mL) 1444.14648.61 222.65 198.55 249.68

TABLE 4 Summary of Statistical Analysis Results of Plasma AtogepantPharmacokinetic Parameters Following Oral Administration of Multi-Dose600 mg Rifampin in Combination with 60 mg Atogepant (Treatment B2, Test)in Comparison to 60 mg Atogepant Administered Alone (Treatment A,Reference), in Healthy Adult Participants (N = 31, PK Population) Ratioof Geometric 90% Lower 90% Upper PK Geometric LSM Means (%) ConfidenceConfidence Parameter Test Reference Test/Ref Interval Interval AUC_(0-∞)1091.54 2809.41 38.85 34.56 43.68 (ng · h/mL) AUC_(0-t) 1121.66 2772.1640.46 36.16 45.28 (ng · h/mL) C_(max) (ng/mL) 454.44 648.61 70.06 60.2781.44

A statistically significant increase in atogepant systemic exposure(2.85-fold for AUC₀₋₂₄ and 2.23-fold for C_(max)) was observed followingcoadministration of single-dose atogepant 60 mg and single-dose rifampin600 mg compared with administration of single-dose atogepant 60 mgalone. Rifampin is an OATP1B1 inhibitor and atogepant metabolism isdependent on the influx of atogepant in the hepatocyte through theOATP1B1 transporter. The increases in atogepant C_(max) and AUC whencoadministered with OATP1B1 inhibitors could be clinically significantand atogepant dose adjustment may be required.

A statistically significant decrease in atogepant systemic exposure (61%for AUC_(0-∞), 60% for AUC_(0-t), and 30% for C_(max)) was observedfollowing coadministration of single dose atogepant 60 mg andmultiple-dose rifampin 600 mg compared with administration ofsingle-dose atogepant 60 mg alone. Rifampin is a strong CYP3A4 inducerand a P-gp inducer, and atogepant is extensively metabolized by CYP3A4and is also a substrate of P-gp. The decreases in atogepant C_(max) andAUC when coadministered with strong CYP3A4 and P-gp inducers could beclinically significant and atogepant dose adjustment may be required.

Safety analyses were based on the safety population (i.e., all patientswho received ≥1 dose of study treatment). Safety measurements includedTEAE recordings, clinical laboratory determinations, vital signparameters, ECG results, and physical examination findings.

All 32 participants received a single 60 mg dose of atogepant on Day 1(Treatment A); 31 participants received co-administration of 60 mgatogepant and 600 mg rifampin on Day 7 followed by 600 mg rifampinalone, once daily, on days 8 to 11 (Treatment B1) and co-administrationo 60 mg atogepant and 600 mg rifampin on day 12 followed by 600 mgrifampin alone on day 13 (Treatment B2). Mean duration of treatment forall participants was 12.6 days.

Overall, atogepant and rifampin were well tolerated during the study.Table 5 provides a summary of AEs by treatment for the safetypopulation. No deaths or SAEs occurred during the study; no participantshad TEAEs that led to discontinuation. A total of 11 (34.4%)participants had TEAEs during the study, 8 (25.8%) after administrationof Treatment B1 and 5 (16.1%) after administration of treatment B2. Noparticipants reported a TEAE after receiving Treatment A.

TABLE 5 Overall Summary of Adverse Events All Treatment A Treatment B1Treatment B2 participants (N = 32) (N = 31) (N = 31) (N = 32) n (%) n(%) n (%) n (%) Treatment-emergent 0 8 (25.8) 5 (16.1) 11 (34.4) adverseevents (TEAE) Deaths 0 0 0 0 Treatment-Emergent 0 0 0 0 Serious AdverseEvents (TESAE) TEAE leading to treatment 0 0 0 0 discontinuation

The most common TEAE (those occurring in at least 2 participants with aspecific treatment) reported after administration of B1 was headache,which occurred in 2 (6.5%) of participants. All TEAEs that were reportedafter administration of Treatment B2 occurred in 1 (3.2%) participanteach.

A total of 5 (15.6% participants had at least one treatment-related TEAEduring the study; 4 (12.9%) after administration of Treatment B1 and 2(6.5%) after administration of Treatment B2. The most common treatmentrelated TEAE was nausea (2 [6.3%] participants, one after Treatment B1and one after Treatment B2). All other treatment-related TEAEs occurredin 1 participant each and included abdominal discomfort, diarrhea,vomiting, abdominal pain, arthralgia, dizziness, headache, andchromaturia.

All TEAEs were mild (10 [31.3%] participants) or moderate (1 [3.1%]participant); no severe TEAEs were reported. Moderate TEAEs includednausea and vomiting reported by 1 participant after administration ofTreatment B 1.

There were no notable changes from baseline in clinical laboratory testresults, vital signs, parameters, and ECG findings. There were noparticipants whose laboratory values met Hy's Law criteria.

Study Treatments, Single-Dose Atogepant Alone or Single-Dose AtogepantCo-Administered with Single- or Multiple-Dose Rifampin

EXAMPLE 2

An open-label, single-sequence drug-drug interaction study was carriedout to evaluate the effect of CYP3A4 inhibition by oral itraconazole(200 mg per day) on the pharmacokinetics of a single oral dose ofatogepant (60 mg) in healthy subjects.

The primary objective of this study was to assess the effects ofmultiple dose itraconazole on the pharmacokinetics of a single dose ofatogepant. The primary endpoints were PK parameters of atogepant derivedfrom plasma concentrations. The secondary objectives of the study wereto assess the safety and tolerability of atogepant and itraconazolegiven alone and in combination, and to establish the correlation betweenconcentrations of atogepant in dried blood sample (DBS) (obtained viafinger stick) and plasma. The secondary endpoints included AEs, clinicallaboratory parameters, vital signs, ECG, and physical examination, andcorrelation of concentrations of atogepant in DBS and plasma.

This study was a single-center, single-sequence, open-label, 2-period PKdrug-interaction study in 40 healthy male and female subjects aged 18through 45 years.

For enrollment into the study, each subject had to meet all of thefollowing inclusion criteria and none of the following exclusioncriteria.

Inclusion Criteria

-   -   Be a healthy male or female, aged 18 through 45 years, inclusive    -   If female, had a negative result from a serum pregnancy test at        screening and a negative result from a serum or urine pregnancy        test on day −1    -   If male, agreed to use an effective method of contraception and        not have their partners become pregnant throughout the study, or        had been sterilized for at least one year    -   If female of childbearing potential, agreed to use an effective        method of contraception and not become pregnant throughout the        study.    -   Be nonsmoking (never smoked or had not smoked within the        previous 2 years)    -   Had a body mass index (BMI) ≥18 kg/m² and ≤30 kg/m².    -   Had a sitting pulse rate ≥60 bpm and ≤100 bpm during the vital        signs assessment at screening.

Exclusion Criteria

-   -   Known hypersensitivity to atogepant or other CGRP receptor        antagonist or itraconazole    -   Clinically significant disease state, in the opinion of the        examining physician, in any body system    -   Sitting systolic blood pressure (SBP) ≥140 mm Hg or ≤90 mm Hg or        sitting diastolic blood pressure (DBP) ≥90 mm Hg or ≤60 mm Hg at        screening    -   Abnormal ECG results thought to be potentially clinically        significant (PCS) or QT prolongation (QTcF ≥450 msec or        uncorrected QT ≥500 msec) according to the investigator    -   Positive test results for anti-human immunodeficiency virus type        1 or 2, hepatitis B surface antigen, or anti-hepatitis C virus        at screening    -   Abnormal and clinically significant results on physical        examination, medical history, serum chemistry, hematology,        coagulation, or urinalysis    -   History of alcohol or other substance abuse within the previous        5 years    -   Positive test results for benzoylecgonine (cocaine), methadone,        barbiturates, amphetamines, benzodiazepines, alcohol,        cannabinoids, opiates, phencyclidine, or cotinine at screening        or Day −1.    -   Participation in any other clinical investigation using an        experimental drug requiring repeated blood or plasma draws        within 60 days of IP administration.    -   Participation in a blood or plasma donation program within 60 or        30 days, respectively, of IP administration    -   Consumption of caffeine within 48 hours, grapefruit-containing        products or vegetables from the mustard greens family (e.g.,        kale, broccoli, watercress, collard greens, kohlrabi, Brussels        sprouts, mustard) within 14 days, or consumption of alcohol        within 72 hours before administration of IP.    -   Any clinical condition or previous surgery that might have        affected the absorption, distribution, biotransformation, or        excretion of atogepant or itraconazole    -   Taken any concomitant medications (including over the counter        medications) within 14 days or hormonal drug products within 30        days before administration of IP    -   Previously taken atogepant or previously participated in an        investigational study of atogepant or MK-8031.    -   Breastfeeding.

Subjects who satisfied the inclusion and exclusion criteria wereassigned to a single fixed-treatment sequence in which they receivedTreatment A followed by Treatment B; there was a 7-day washout periodbetween treatments.

-   -   Treatment A: Single oral 60 mg dose of atogepant (tablet) under        fasted conditions on Day 1    -   Treatment B        -   Days 8-14: Itraconazole 200 mg (tablet) orally once daily            under fed conditions.        -   Day 15: Itraconazole 200 mg coadministered with atogepant 60            mg (tablet) under fasted conditions.        -   Days 16 to 17: Itraconazole 200 mg (tablet) once daily under            fed conditions.

Atogepant was administered in the fasted state in this study.Administration of itraconazole with food enhances its bioavailability.Accordingly, to maximize the CYP3A4 inhibition effect, itraconazole wasadministered with food on all the itraconazole treatment days except day15. On day 15, both itraconazole and atogepant were administered underfasted state. Fasted state administration of itraconazole on Day 15 wasunlikely to affect the CYP3A4 inhibition effect due to the attainment ofsteady state (of CYP3A4 activity) and long T_(1/2) of itraconazole (34to 42 hours) following repeat dose administration.

The total duration of study participation for each subject wasapproximately 48 days excluding the screening visit (Day −1 through Day47). The study included 8 overnight stays.

The mean age of participants was 34.8 years with a range from 19 to 45years. Eighteen (45%) subjects were male and 22 (55%) were female. Atotal of 33 (82.5% subjects were white and 7 (17.5%) were black orAfrican American. Overall, 37 (92.5%) were Hispanic or Latino and 3(7.5%) were not Hispanic or Latino. Mean (SD) BMI was 27.41 (2.47)kg/m².

Mean plasma concentrations of atogepant after the administration of 60mg either alone or in the presence of steady state itraconazole arepresented in FIG. 3 . A semilogarithmic plot of the mean plasmaconcentrations of atogepant is presented in FIG. 4 . Mean (SD) PKparameters and the results of statistical analysis are provided in Table6.

TABLE 6 PK Parameters of Atogepant Following Treatment A (60 mgsingle-dose Atogepant) and Treatment B (60 mg single-dose Atogepant +Itraconazole) in Healthy Subjects Atogepant Atogepant + AloneItraconazole GM Ratio (%) (Treatment A; (Treatment B; Treatment B/ PKParameter N = 40) N = 40) Treatment A 90% CI C_(max) (ng/mL) 740 (231)1580 (469) 215.11 195.25, 236.99 AUC_(0-t) (ng · h/mL) 3440 (1030) 18500(4860) 543.26 501.54, 588.45 AUC_(0-∞) (ng · h/mL) 3470 (1040) 18900(4990) 550.78 508.64, 596.42 T_(max) (h) 2.0 (1.0-3.0)* 3.0 (1.5-4.0)*  1.0** — λ_(z) (1/h) 0.0825 (0.0412) 0.0496 (0.0122) — — T_(1/2) (h)11.2 (7.78) 14.9 (3.96) — — CL/F (L/h) 19.2 (7.49) 3.46 (1.18) — — Vz/F(L) 292 (175) 73.4 (34.4) — — *Median (min-max)

** Difference of Medians

AUC_(0-t)=area under the plasma concentration versus time curve fromtime 0 to time t; AUC_(0-∞)=area under the plasma concentration versustime curve from time 0 to infinity; CI=confidence interval;CL/F=apparent total body clearance of drug from plasma afterextravascular administration; C_(max)=maximum plasma drug concentration;GM=geometric mean; λ_(z)=terminal elimination rate constant;T_(1/2)=terminal elimination half-life; T_(max)=time to reach maximumplasma drug concentration; V_(Z)/F=apparent volume of distributionduring the terminal phase after extravascular administration.

The C_(max) and AUC of atogepant increased by 2.15-fold and 5.5-fold,respectively, due to inhibition of CYP3A4 by itraconazole. Such anincrease in exposure of atogepant due to CYP3A4 inhibition could beclinically significant and atogepant dose adjustment may be needed whenconcomitantly administered with strong CYP3A4 inhibitors.

Systemic clearance of atogepant decreased from 19.2 L/h following itsadministration alone to 3.46 L/h following its administration in thepresence of steady state itraconazole. Accordingly, T_(1/2) of atogepantincreased from 11.2 hours following its administration alone to 14.9hours due to CYP3A4 inhibition by itraconazole.

Overall, each treatment was well-tolerated. Five TEAEs were reported (2subjects experienced dizziness [atogepant alone], 2 subjects experiencedheadache [itraconazole alone], and 1 subject experienced constipation[itraconazole alone]). None of the TEAEs was reported as an SAE, and allTEAEs were mild in intensity. No TEAEs led to permanent discontinuationof study treatment. No deaths occurred during the study. There were nopostbaseline laboratory findings, vital signs, or ECGs that were PCSduring the study.

Overall, itraconazole at steady state had a clinically significanteffect on the pharmacokinetics of atogepant. These results suggest thatCYP3A4 inhibition by itraconazole or other strong CYP3A4 inhibitors willresult in a clinically significant increase in the exposure ofatogepant. Atogepant dose reduction may be needed when concomitantlyadministered with strong CYP3A4 inhibitors. Each treatment regimen waswell tolerated in healthy subjects.

EXAMPLE 3

A multicenter, non-randomized, open-label, parallel-group, single-dosestudy was carried out to evaluate the PK, safety, and tolerabilityprofiles of atogepant in participants with impaired hepatic function andmatched healthy participants with normal hepatic function after a single60-mg oral dose of atogepant. The primary outcome measures were PKparameters of atogepant derived from plasma concentrations. Safetymeasures were AEs, clinical laboratory determinations, vital signparameters, electrocardiographic results, and physical examinationfindings.

In this study, participants with normal hepatic function andparticipants with hepatic impairment (mild, moderate, or severeaccording to the Child-Pugh classification) received a single, oral,60-mg tablet of atogepant on Day 1 with 240 mL of water at the studycenter under fasted conditions. PK blood samples were collected for upto 72 hours after dose administration. The total duration of studyparticipation for each participant was 5 days (Day −1 to Day 4),excluding the screening visit. Participants were admitted in the clinicon Day −1 and remained in the clinic until Day 4. Participants withmoderate hepatic impairment were enrolled after 4 participants with mildhepatic impairment completed the study; participants with severe hepaticimpairment were enrolled after 4 participants with moderate hepaticimpairment completed the study. Participants with normal hepaticfunction were recruited after all patients with hepatic impairment wereenrolled in the study. The safety and tolerability of atogepant wasestablished in each group before the subsequent group was enrolled.

Participants had an EOS visit on or within 7 days of the final PK sampleon Day 4. Participants also had a safety follow-up visit on day 30 forsafety assessments.

Planned enrollment was 32 participants: 24 with hepatic impairment (8mild, 8 moderate, and 8 severe) and 8 with normal hepatic function. Allparticipants were 18 to 80 years of age with BMI ≥18 kg/m² and ≤42kg/m², sitting pulse rate ≥50 bpm and ≤100 bpm, and QTcF <470 msec.Participants with hepatic impairment had to have a Child-Pugh score of≤12 and were not to be included if sitting systolic blood pressure was≥165 mmHg or ≤95 mmHg or sitting diastolic blood pressure was ≥100 mmHgor ≤50 mmHg at screening. Participants with normal hepatic function werenot to be included if sitting systolic blood pressure was ≥140 mmHg or≤90 mmHg or sitting diastolic blood pressure was ≥90 mmHg or ≤50 mmHg atscreening.

Participants were enrolled into four groups: Group I (Mild HepaticImpairment); Group II (Moderate Hepatic Impairment); Group III (SevereHepatic Impairment); and Group IV (Normal Hepatic Impairment).Participants with normal hepatic function were recruited after theparticipants with hepatic impairment were enrolled in the study so thatparticipants could be matched as closely as possible by age range,weight range, and gender among groups. Participants were matchedspecifically according to rage range, not exceeding 5 years between themeans of the normal group and the 3 impaired hepatic function groupscombined; weight range, which deviated <20% between the means of thenormal group and the 3 impaired hepatic function groups combined; andgender, as much as possible to match the ratio of the normal group tothe 3 impaired hepatic function groups combined.

A total of 32 participants were enrolled: 8 with normal hepaticfunction, 8 with mild hepatic impairment, 8 with moderate hepaticimpairment, and 8 with severe hepatic impairment. All participantscompleted the study through the safety follow-up period. No participantsprematurely discontinued.

The mean age of the Safety Population was 58.8 years (range: 45 to 72years), two-thirds of the population were male, the majority ofparticipants (87.5%) were white, and the mean BMI was 30.72 kg/m². Thedemographic characteristics were similar across the 4 hepatic functiongroups except for ethnicity: three-fourths of the participants in themoderate hepatic impairment group were non-Hispanic/non-Latino, whereasin the other hepatic function groups non-Hispanic/non-Latinoparticipants made up one-fourth to half of the participants in eachgroup. The observed difference in distribution of ethnicity across thegroups is unlikely to impact the results of the study.

No participants in the normal hepatic function group had a medicalhistory of any hepatobiliary disorders, compared with a positive historyof hepatobiliary disorders for 6/8 participants in the mild hepaticimpairment cohort, 8/8 in the moderate hepatic impairment cohort, and8/8 in the severe hepatic impairment cohort.

Participants received a single, oral, 60 mg tablet of atogepant. Eachparticipant received only one dose of the study intervention.Participants received the atogepant tablet with 240 mL of water at thestudy center under fasted conditions. Following dose administration,participants continued their fast and remained seated upright and awakefor 4 hours.

From 14 days before Day 1 and until all study procedures were completed,participants were to refrain from consuming grapefruit, grapefruitjuice, and vegetables from the mustard green family (e.g., kale,broccoli, watercress, collard greens, kohlrabi, Brussels sprouts,mustard). From 48 hours before administration of the study interventionand until all study procedures were completed, participants were torefrain from consuming xanthine-containing compounds (products withcaffeine, which included, but were not limited to, coffee, tea, softdrinks, energy sports drinks, and chocolate). Alcoholic beverages werenot to be allowed from 72 hours before dosing until completion of PKblood sampling; furthermore, the participants with alcohol-induced livercirrhosis were to abstain from alcohol for at least one week prior toadministration of the study intervention and during the entire study.Participants were not to engage in strenuous activity at any time duringthe study.

Sampling for atogepant plasma concentrations was done starting on Day 1at 0 hour (predose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36,48, and 72 hours post dose.

The mean plasma atogepant concentration-time profiles on a linear scalein participants with varying degrees of hepatic impairment and withnormal hepatic function are presented in FIG. 5A. The correspondingsemi-logarithmic plot is provided in FIG. 5B. A summary of the mean PKparameters for atogepant when administered to participants with varyingdegrees of hepatic impairment and to participants with normal hepaticfunction is presented in Table 7.

TABLE 7 Mean (±SD) Atogepant Pharmacokinetic Parameters Following SingleDose Oral Administration of Atogepant 60 mg in Participants with Mild,Moderate, or Severe Hepatic Impairment and in Participants with NormalHepatic Function, PK Population Mild Hepatic Moderate Hepatic SevereHepatic Normal Hepatic Impairment Group Impairment Group ImpairmentGroup Function Group PK Parameter (N = 8) (N = 8) (N = 8) (N = 8)C_(max) (ng/mL) 666.30 ± 372.13 528.60 ± 227.13 524.87 ± 197.18  588.65± 248.49 T_(max) (h)^(a) 1.76 (1.00-4.00) 1.50 (1.00-6.00) 1.00(0.50-3.00) 1.75 (1.00-3.00) AUC_(0-t) (ng · h/mL) 3472.65 ± 1424.903270.13 ± 1693.04 3797.07 ± 1397.20 2757.92 ± 918.96 AUC_(0-∞) (ng ·h/mL) 3495.31 ± 1425.30 3313.94 ± 1684.18 3836.32 ± 1439.69 2779.79 ±924.38 AUC % 0.73 ± 0.42 1.70 ± 1.44 0.87 ± 0.65  0.81 ± 0.23 λ_(z)(1/h) 0.0906 ± 0.0300 0.0781 ± 0.0431 0.0998 ± 0.0242  0.0819 ± 0.0289T_(1/2) (h) 8.70 ± 4.06 11.90 ± 7.60  7.54 ± 2.95  9.40 ± 3.24 CL/F(L/h) 19.42 ± 6.60 21.33 ± 8.06  17.33 ± 5.40  24.20 ± 9.42 Vz/F (L)249.10 ± 161.40 404.03 ± 405.78 176.59 ± 47.48  301.18 ± 77.01^(a)Median (range)

Differences in median T_(max) for participants with mild, moderate, orsevere hepatic impairment as compared with participants with normalhepatic function were 0 hr, 0.25 hr, and 0.75 hr, respectively. The meanterminal elimination half life of atogepant was generally similar inparticipants with hepatic impairment and in participants with normalhepatic function.

Table 8 provides a statistical comparison of the PK parameters forparticipants with varying degrees of hepatic impairment and participantswith normal hepatic function including the ratio of geometric means and90% CI.

TABLE 8 Summary of Statistical Analysis of Plasma Atogepant PKParameters Following Single Dose Oral Administration of 60 mg Atogepantin Participants with Mild, Moderate, or Severe Hepatic Impairment (test)as Compared with Participants with Normal Hepatic Function (reference),PK Population Geometric Least Ratio of Hepatic PK Squares Mean GeometricMeans 90% 90% Group Parameter Test Reference Test/Reference Lower CIUpper CI Mild C_(max) 586.89 538.55 108.97 72.72 163.31 Impairment(ng/mL) AUC_(0-t) 3249.63 2612.14 124.40 89.78 172.38 (ng · h/mL)AUC_(0-∞) 3273.58 2633.43 124.31 89.83 171.83 (ng · h/mL) ModerateC_(max) 474.85 538.55 88.17 58.83 132.14 Impairment (ng/mL) AUC_(0-t)2976.87 2612.14 113.96 82.25 157.91 (ng · h/mL) AUC_(0-∞) 3028.572633.43 115.00 83.20 158.97 (ng · h/mL) Severe C_(max) 515.45 538.5595.71 63.86 143.44 Impairment (ng/mL) AUC_(0-t) 3601.63 2612.14 137.8899.51 191.05 (ng · h/mL) AUC_(0-∞) 3633.22 2633.43 137.97 99.81 190.71(ng · h/mL)

Participants with mid hepatic impairment had 9% higher C_(max) and 24%higher AUC when compared with participants with normal hepatic functionafter administration of a single oral dose of 60 mg atogepant.Participants with moderate hepatic impairment had a 12% lower C_(max)but 14%-15% higher AUC; while those with severe hepatic impairmentshowed a decrease of 4% in atogepant C_(max) with a 38% increase inatogepant AUC, as compared with participants with normal hepaticfunction.

Protein binding blood samples were collected from all participantsstarting on Day 1 at 0 hour (predose) and at 2 hours post dose. Thepre-dose samples collected prior to dosing for each participant wereexternally spiked with known quantities of atogepant. Percent boundatogepant was determined in the 2-hour sample using direct measurementof the atogepant concentrations in the blood sample. Percentage of boundatogepant is summarized in Table 9.

TABLE 9 Summary of Atogepant Plasma Protein-Binding (Expressed asPercent Bound) in Participants with Mild, Moderate, or Severe HepaticImpairment and in Participants with Normal Hepatic Function FollowingSingle Dose Oral Administration of 60 mg Atogepant, PK Population 0 hrHepatic Group (Predose) 2 hr Mild-impaired (N = 8) 97.03 ± 0.75 97.36 ±0.70 Moderate-Impaired (N = 8) 96.60 ± 0.94 97.05 ± 0.62 Severe-Impaired(N = 8) 94.48 ± 1.21 95.34 ± 0.85 Normal Hepatic Function (N = 8) 97.89± 0.54 98.21 ± 0.46

Plasma protein binding did not change substantially in participants withimpaired hepatic function when compared with participants with normalhepatic function. In participants with mild, moderate, or severe hepaticimpairment administered a single oral dose of 60 mg atogepant,percentage of plasma protein-bound atogepant was 97.4%, 97.1%, and95.3%, respectively, as compared with 98.2% in participants with normalhepatic function. Plasma protein binding was generally similar acrossall hepatic-impairment groups as well as in participants with normalhepatic function.

Overall, there was no clinically relevant change in the PK of atogepantin participants with mild, moderate, or severe hepatic impairment.Compared with participants with normal hepatic function, the maximumplasma concentrations of atogepant were generally unchanged inparticipants with mild, moderate, or severe hepatic impairment (+9%,−12%, and −4%, respectively). The overall extent of atogepant systemicexposures (AUC) were slightly higher (14% to 38%) in participants withhepatic impairment as compared with participants with normal hepaticfunction, but these changes are unlikely to be clinically relevant.

Atogepant was well tolerated by participants in all hepatic functiongroups. One AE was reported during this study, which was mild andtransient. No SAEs or AEs leading to premature discontinuation werereported and no participants died. No clinically relevant changes inclinical laboratory parameters, vital signs, or ECG values were observedin any hepatic function group. No participant met the potential Hy's lawcriteria. No safety concerns were identified relative to administrationof a single 60-mg dose of atogepant to participants with hepaticimpairment.

EXAMPLE 4

Population pharmacokinetic modeling was conducted to evaluate theco-administration of atogepant with moderate CYP3A4 inhibitors (e.g.,cyclosporine, ciprofloxacin, fluconazole, fluvoxamine, grapefruit juice)or weak CYP3A4 inhibitors (e.g., cimetidine, esomeprazole). Modelingsuggested that moderate CYP3A4 inhibitors increase atogepant AUC by1.7-fold, and that mild CYP3A4 inhibitors increase atogepant AUC by1.1-fold. The changes in atogepant exposure when co-administered withweak or moderate CYP3A4 inhibitors are not expected to be clinicallysignificant.

EXAMPLE 5

A phase 1, open-label, 2-intervention, single-sequence, nonrandomized,crossover, drug-drug interaction study was conducted to evaluate theeffects of multiple-dose esomeprazole magnesium 40 mg onpharmacokinetics (PK) and safety of co-administered single-doseatogepant 60 mg in healthy adults.

In this study, healthy adult participants received single-dose oralatogepant 60 mg on day 1, followed by once-daily esomeprazole 40 mg ondays 7-13, co-administered with single-dose atogepant on day 12. Samplesfor atogepant PK analysis were collected on days 1 and 12. PK parameterscalculated from atogepant plasma concentrations included peak plasmaconcentration (C_(max)); time to C_(max) (t_(max)); area under plasmaconcentration-time curve from time 0 to time 5 (AUC_(0-t)) and from time0 to infinity (AUC_(0-∞)). PK parameters of atogepant alone vs.co-administered with esomeprazole were compared using a mixed-effectsmodel. Statistical significance was achieved if 90% confidence intervals(CIs) for geometric least squares mean ratios (GMRs) of PK parametervalues for atogepant co-administered with esomeprazole to atogepantadministered alone were within 80%-125%.

Thirty-two participants (mean age 30.8 years; 50% male) were enrolled;29 (90.6%) completed the study. Median plasma atogepant t_(max) wasdelayed 1.5 hours, from 1.51 hours for atogepant alone to 3.00 hours forcoadministration with esomeprazole. GMRs (90% CI) were 76.63(69.19-86.11) for C_(max); 91.61 (93.67-100.29) for AUC_(0-t); and 92.04(94.12-100.71) for AUC_(0-∞); only the change in C_(max) wasstatistically significant. Treatment-emergent adverse events weregenerally infrequent and mild in intensity, except one event each ofpresyncope (moderate) and elective abortion (severe).

Coadministration with esomeprazole reduced the rate (23% reducedC_(max); increased t_(max)) but not the extent of atogepant absorption;this interaction is unlikely to have clinical significance. Atogepant 60mg alone or co-administered with esomeprazole magnesium 40 mg was safeand tolerated in healthy participants.

EXAMPLE 6

A phase 1, single-center, single-sequence, open-label, 2-intervention,drug-drug interaction study was conducted to evaluate the effects ofP-glycoprotein (P-gp) inhibition by quinidine gluconate onpharmacokinetics (PK) and safety of atogepant. In this study, healthyadults received atogepant 60 mg on day 1, quinidine gluconate 324 mgtwice daily on Day 8, quinidine gluconate 648 mg twice-daily on days9-12, and atogepant 60 mg co-administered on day 11. Plasma samples werecollected on days 1 and 11.

Atogepant PK parameters calculated were peak plasma concentration(C_(max)); time to C_(max) (t_(max)); and area under plasmaconcentration—time curve from time 0 to time t (AUC_(0-t)) and infinity(AUC_(0-∞)). PK parameters of atogepant co-administered with quinidinegluconate vs. atogepant administered alone were compared using amixed-effects model. Statistical significance was achieved if 90%confidence intervals (Cis) for least squares geometric mean ratios(GMRs) of PK parameter values for atogepant co-administered withquinidine gluconate to atogepant administered alone were within80%-125%. Safety assessments included clinical laboratory values, vitalsigns, electrocardiograms, and treatment-related adverse events (TEAEs).

Of 33 enrolled participants (mean age 30.3 years, 72.7% males), 23(69.7%) completed the study. 10 discontinued because oftreatment-emergent adverse events (TEAEs; all electrocardiogram QTprolongation during quinidine gluconate administration). Atogepantmedian t_(max) was 1.50 hours with or without quinidine gluconateadministration. GMRs (90% CI) were 104.41 (89.17-122.25) for C_(max),120.49 (110.21-142.88) for AUC_(0-t), and 125.91 (110.56-143.40) forAUC_(0-∞); changes in AUC were statistically significant. TEAEs weremostly related to quinidine gluconate administration.

Atogepant C_(max) increased 4.4% and AUC increased approximately 25%when co-administered with quinidine gluconate. However, these changesare not expected to be clinically significant. Atogepant 60 mg was safeand well tolerated when administered alone or co-administered withquinidine gluconate in healthy participants.

EXAMPLE 7

The efficacy of atogepant for the preventive treatment of episodicmigraine in adults was demonstrated in two randomized, multicenter,double-blind, placebo-controlled studies (Study 1 and Study 2). Thestudies enrolled patients with at least a 1-year history of migrainewith or without aura, according to the International Classification ofHeadache Disorders (ICHD-3) diagnostic criteria.

In Study 1 (NCT03777059), 910 patients were randomized 1:1:1:1 toreceive atogepant 10 mg (N=222), atogepant 30 mg (N=230), atogepant 60mg (N=235), or placebo (N=223), once daily for 12 weeks. In Study 2(NCT02848326), 652 patients were randomized 1:2:2:2 to receive atogepant10 mg (N=94), atogepant 30 mg (N=185), atogepant 60 mg (N=187), orplacebo (N=186), once daily for 12 weeks. In both studies, patients wereallowed to use acute headache treatments (i.e., triptans, ergotaminederivatives, NSAIDs, acetaminophen, and opioids) as needed. The use of aconcomitant medication that acts on the CGRP pathway was not permittedfor either acute or preventive treatment of migraine. The studiesexcluded patients with myocardial infarction, stroke, or transientischemic attacks within six months prior to screening.

Study 1

The primary efficacy endpoint was the change from baseline in meanmonthly migraine days (MMD) across the 12-week treatment period.Secondary endpoints included the change from baseline in mean monthlyheadache days, the change from baseline in mean monthly acute medicationuse days, the proportion of patients achieving at least a 50% reductionfrom baseline in mean MMD (3-month average), the change from baseline inmean monthly Activity Impairment in Migraine-Diary (AIM-D) Performanceof Daily Activities (PDA) domain scores, the change from baseline inmean monthly AIM-D Physical Impairment (PI) domain scores, across the 12week treatment period, and the change from baseline at Week 12 forMigraine Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1)Role Function-Restrictive (RFR) domain scores.

The AIM-D evaluates difficulty with performance of daily activities (PDAdomain) and physical impairment (PI domain) due to migraine, with scoresranging from 0 to 100. Higher scores indicate greater impact ofmigraine, and reductions from baseline indicate improvement. The MSQv2.1 Role Function-Restrictive (RFR) domain score assesses how oftenmigraine impacts function related to daily social and work-relatedactivities over the past 4 weeks, with scores ranging from 0 to 100.Higher scores indicate lesser impact of migraine on daily activities,and increases from baseline indicate improvement.

Patients had a mean age of 42 years (range 18 to 73 years), 89% werefemale, 83% were White, 14% were Black, and 9% were of Hispanic orLatino ethnicity. The mean migraine frequency at baseline wasapproximately 8 migraine days per month and was similar across treatmentgroups. A total of 805 (88%) patients completed the 12-week double-blindstudy period. Key efficacy results of Study 1 are summarized in Table10.

TABLE 10 Efficacy Endpoints in Study 1 Atogepant Atogepant Atogepant 10mg 30 mg 60 mg Placebo N = 214 N = 223 N = 222 N = 214 Monthly MigraineDays (MMD) across 12 weeks Baseline 7.5 7.9 7.8 7.5 Mean change frombaseline −3.7 −3.9 −4.2 −2.5 Difference from placebo −1.2 −1.4 −1.7p-value <0.001 <0.001 <0.001 Monthly Headache Days across 12 weeksBaseline 8.4 8.8 9.0 8.4 Mean change from baseline −3.9 −4.0 −4.2 −2.5Difference from placebo −1.4 −1.5 −1.7 p-value <0.001 <0.001 <0.001Monthly Acute Medication Use Days across 12 weeks Baseline 6.6 6.7 6.96.5 Mean change from baseline −3.7 −3.7 −3.9 −2.4 Difference fromplacebo −1.3 −1.3 −1.5 p-value <0.001 <0.001 <0.001 ≥50% MMD Respondersacross 12 weeks % Responders 56 59 61 29 Difference from placebo (%) 2730 32 p-value <0.001 <0.001 <0.001 MSQ v2.1 RFR Domain* at week 12Baseline 44.9 44.0 46.8 46.8 Mean change from baseline 30.4 30.5 31.320.5 Difference from placebo 9.9 10.1 10.8 p-value <0.001 <0.001 <0.001AIM-D PDA Domain** across 12 weeks Baseline 15.5 16.9 15.9 15.2 Meanchange from baseline −7.3 −8.6 −9.4 −6.1 Difference from placebo −1.2−2.5 −3.3 p-value NS^(†) <0.001 <0.001 AIM-D PI Domain*** across 12weeks Baseline 11.7 13.0 11.6 11.2 Mean change from baseline −5.1 −6.0−6.5 −4.0 Difference from placebo −1.1 −2.0 −2.5 p-value NS^(†) 0.002<0.001 *Migraine Specific Quality of Life Questionnaire version 2.1 RoleFunction-Restrictive domain score **Activity Impairment inMigraine-Diary Performance of Daily Activities domain score ***ActivityImpairment in Migraine-Diary Physical Impairment domain score ^(†)Notstatistically significant (NS)

The mean change from baseline in MMD in Study 1 is shown in FIG. 6 .FIG. 7 shows the distribution of change from baseline in mean monthlymigraine days (MMD) across the 12-week treatment period, in 2-dayincrements, by treatment group. A treatment benefit over placebo for alldoses of atogepant is seen across a range of mean changes from baselinein MMD.

Study 2

The primary efficacy endpoint was the change from baseline in meanmonthly migraine days across the 12-week treatment period.

Patients had a mean age of 40 years (range: 18 to 74 years), 87% werefemale, 76% were white, 20% were Black, and 15% were of Hispanic orLatino ethnicity. The mean migraine frequency at baseline wasapproximately 8 migraine days per month. A total of 541 (83%) patientscompleted the 12-week double-blind study period.

In Study 2, there was a significantly greater reduction in mean monthlymigraine days across the 12-week treatment period in all three atogepanttreatment groups, compared with placebo, as summarized in Table 11.

TABLE 11 Efficacy Endpoints in Study 2 Atogepant Atogepant Atogepant 10mg 30 mg 60 mg Placebo N = 92 N = 182 N = 177 N = 178 Monthly MigraineDays (MMD) across 12 weeks Baseline 7.6 7.6 7.7 7.8 Mean change frombaseline −4.0 −3.8 −3.6 −2.8 Difference from placebo −1.1 −0.9 −0.7p-value 0.024 0.039 0.039 Monthly Headache Days across 12 weeks Baseline8.9 8.7 8.9 9.1 Mean change from baseline −4.3 −4.2 −3.9 −2.9 Differencefrom placebo −1.4 −1.2 −0.9 p-value 0.024 0.039 0.039

FIG. 8 shows the mean change from baseline in MMD in Study 2. Patientstreated with atogepant had greater mean decreases from baseline in MMDacross the 12-week treatment period compared to patients who receivedplacebo. FIG. 9 shows the distribution of change from baseline in meanMMD across the 12-week treatment period, in 2-day increments, bytreatment group. A treatment benefit over placebo for all doses ofatogepant is seen across a range of mean changes from baseline in MMD.

EXAMPLE 8

The safety of atogepant was evaluated in 1958 patients with migraine whoreceived at least one dose of atogepant. Of these, 839 patients wereexposed to atogepant once daily for at least 6 months, and 487 patientswere exposed for 12 months. In the 12-week, placebo-controlled clinicalstudies (Study 1 and Study 2, discussed above in Example 7), 314patients received at least one dose of atogepant 10 mg once daily, 411patients received at least one dose of atogepant 30 mg once daily, 417patients received at least one dose of atogepant 60 mg once daily, and408 patients received placebo. Approximately 88% were female, 80% wereWhite, 17% were Black, and 12% were of Hispanic or Latino ethnicity. Themean age at study entry was 41 years (range 18 to 74 years).

The most common adverse reactions (incidence at least 4% and greaterthan placebo) are nausea, constipation, and fatigue.

Table 12 summarizes the adverse reactions that occurred during Study 1and Study 2.

TABLE 12 Adverse Reactions Occurring with an Incidence of at least 2%for Atogepant and Greater than Placebo in Studies 1 and 2 AtogepantAtogepant Atogepant Placebo 10 mg 30 mg 60 mg (N = 408) % (N = 314) % (N= 411) % (N = 417) % Nausea 3 5 6 9 Constipation 1 6 6 6Fatigue/Somnolence 3 4 4 6 Decreased Appetite <1 2 1 2

The adverse reactions that most commonly led to discontinuation inStudies 1 and 2 were constipation (0.5%), nausea (0.5%), andfatigue/somnolence (0.5%).

Liver Enzyme Elevations

In Study 1 and Study 2, the rate of transaminase elevations over 3 timesthe upper limit of normal was similar between patients treated withatogepant (1.0%) and those treated with placebo (1.8%). However, therewere cases with transaminase elevations over 3 times the upper limit ofnormal that were temporally associated with atogepant treatment; thesewere asymptomatic, and resolved within 8 weeks of discontinuation. Therewere no cases of severe liver injury or jaundice.

Decreases in Body Weight

In Studies 1 and 2, the proportion of patients with a weight decrease ofat least 7% at any point was 2.8% for placebo, 3.8% for atogepant 10 mg,3.2% for atogepant 30 mg, and 4.9% for atogepant 60 mg.

EXAMPLE 9

A single-center, randomized, open-label, single-dose, 2-periodcross-over study was conducted to evaluate the effect of a high-fat mealon the systemic exposure of atogepant following single-doseadministration of an immediate release (IR) tablet in healthy adultparticipants. Secondary objectives were to evaluate the secondary PKparameters of atogepant following single-dose administration of an IRtablet formulation of atogepant in healthy participants under fasted andfed conditions; and to evaluate the safety and tolerability profiles ofsingle-dose atogepant in healthy adult participants under fed and fastedconditions.

Twenty healthy adult male and female participants, aged 18-45 years,received a single 60 mg dose of atogepant after an overnight fast orfollowing a high-fat meal (served 30 minutes prior to dosing) with awashout period of 7 days between interventions. Plasma samples werecollected pre-dose and at predetermined time intervals up to 48 hoursafter dosing. Atogepant plasma concentrations were determined using avalidated LC-MS/MS assay and the pharmacokinetic (PK) parameters werecalculated using WinNonlin. A linear mixed-effects model with sequence,study intervention, and period as fixed effects, and participant nestedwithin sequence as a random effect was used to compare the naturallogarithm transformed values of atogepant PK parameters AUC_(0-t),AUC_(0-inf), and C_(max). Safety was monitored via ECGs, vital signs,clinical labs, and adverse events.

Participants were randomly assigned to receive Study Intervention A(single dose of 60-mg atogepant, IR formulation, 1×60 mg atogepanttablet; fed conditions) or Study Intervention B (single dose of 60-mgatogepant, IR formulation, 1×60 mg atogepant tablet; fasted conditions).

Screening occurred within 21 days before dosing (Days −21 to −1). Thestudy intervention period was scheduled for a total of 11 days (Days −1to 10), and the follow-up visit occurred with serum chemistry on day 38(±3), (30 [±3] days after the last dose on Day 8). PK blood samples foranalysis of plasma atogepant concentrations were collected starting onDays 1 (period 1) and 8 (period 2); at 0 hour (predose) and 0.5, 1, 1.5,2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose.

Overall, 20 participants were randomly assigned to receive StudyInterventions A and B in 1 of 2 sequences, with a washout period of atleast 7 days between each study intervention, as shown in Table 13.Nineteen (95.0%) participants completed the study and 1 (5.0%)participant was discontinued from the study on Day 7 (period 2) due to asignificant protocol deviation.

TABLE 13 Study Intervention Sequences Period 1 Period 2 Sequence I StudyIntervention A Study Intervention B Sequence II Study Intervention BStudy Intervention A

-   Study Intervention A: Single Dose of 60-mg atogepant, immediate    release formulation (1×60 mg atogepant tablet), fed conditions.-   Study Intervention B: Single Dose of 60-mg atogepant, immediate    release formulation (1×60 mg atogepant tablet), fasted conditions.

Participants were healthy, male or female, aged 18 through 45 years,inclusive, with a body mass index ≥18 and ≤30 kg/m², and sitting pulserate ≥40 and ≤100 bpm during the vital sign assessment at the ScreeningVisit. Participants must also have been nonsmoking and a nonuser ofnicotine-containing products (never smoked or used nicotine-containingproducts or have not smoked or used nicotine-containing products,including eCigarettes, within the previous 6 months before studyintervention administration). Twenty healthy participants with a meanage of 31.9 years (range: 23 to 44 years) were enrolled. The majority ofparticipants were male (13 of 20 participants, 65.0%). Participants wereblack or African American (11 of 20 participants, 55.0%), white (8 of 20participants, 40.0%), and of multiple races (1 of 20 participants,5.0%). The mean (SD) weight was 72.95 (9.264) kg and mean (SD) body massindex was 24.15 (2.368) kg/m². Demographic and baseline characteristicswere comparable across sequences, and the same for the PK and safetypopulations.

Atogepant plasma concentration data were analyzed for 19 and 20participants for the fed and fasted study interventions, respectively.

The mean concentration-time profiles for plasma atogepant aftersingle-dose administration of the 1×60 mg atogepant IR formulation underfed conditions (Study Intervention A) and under fasted conditions (StudyIntervention B) are presented in FIG. 10 (linear scale±SD, withsemilogarithmic scale insert). Plasma atogepant PK parameters aresummarized in Table 14. Although mean C_(max) and AUC were lower foratogepant administered under fed conditions than under fastedconditions, median T_(max) and T_(lag) values were the same and meant_(t1/2), CL/F, and V_(z)/F were similar for the two studyinterventions. Boxplots of plasma atogepant PK parameters are presentedin FIG. 11 (AUC_(0-t) and AUC_(0-inf)) and FIG. 12 (C_(max)).

TABLE 14 Mean (SD) Plasma Atogepant PK Parameters (PK Population) StudyStudy Intervention A: Intervention B: Atogepant 1 × Atogepant 1 × 60 mg,Fed 60 mg, Fasted Parameter (N = 19^(a)) (N = 20) AUC_(0-t) (h*ng/mL)3088.54 (2207.78) 3460.48 (1564.37) AUC_(0-inf) (h*ng/mL) 3204.51(2246.31) 3486.77 (1568.33) N = 18 C_(max) (ng/mL) 593.75 (309.74)731.64 (288.61) T_(max) ^(b) 2.01 (1.01-6.01) 2.01 (1.01-4.01) T_(lag)^(b) 0.00 (0.00-1.01) 0.00 (0.00-0.00) λ_(z) (1/h) 0.0840 (0.02862)0.0799 (0.02962) N = 18 t_(t/2) (h) 9.41 (4.13) 9.71 (3.30) N = 18 CL/F(L/h) 26.10 (15.20) 21.03 (9.87) N = 18 V_(z)/F (L) 368.01 (299.19)298.95 (192.93) N = 18 ^(a)Unless otherwise indicated ^(b)Median(minimum-maximum) reported for T_(max) and T_(lag)

TABLE 15 Summary of Food-Effect Analysis (PK Population) Ratios of GLSMs(%) Intra-CV % Parameter Fed (Test) Fasted (Ref) 90% A B Inter- (units)N GLSM N GLSM Test/Ref CIs (Test) (ref) CV % AUC_(0-t) 19 2558.05 203130.99 81.70 71.57- 23.80^(a) 50.29 (h*ng/mL) 93.26 AUC_(0-inf) 182606.55 20 3158.38 82.53 71.77- 34.50 3.62 49.89 (h*ng/mL) 94.89 C_(max)19 527.40 20 677.01 77.90 64.14 40.75 29.73 30.32 (ng/mL) 94.62Parameter Fed (Test) Fasted (ref) Median of Paired Differences (units) NMedian N Median (Test Minus Reference) Tmax (h) 19 2.01 20 2.01 0.50^(a)Results for AUC_(0-t) were provided from a model without therepeated statement (which allowed the variance of the response to varyacross different study conventions), because the model did not converge.GLSM = Geometric least Square Mean

-   Linear mixed effects model with natural logarithm-transformed values    of AUC_(0-t), AUC_(0-inf), and C_(max), as the dependent variable    and terms for study intervention, sequence, and period as fixed    independent variables and participant nested in sequence as a random    effect. The median of the difference in T_(max) is also presented.-   Study intervention was a single dose of 60-mg atogepant    immediate-release formulation (1×60-mg tablet) under fed and fasted    conditions.

A food effect was demonstrated on the pharmacokinetics of atogepant60-mg IR tablet formulation. The food effect, although statisticallysignificant, was mild. Administration of the atogepant 60-mg IR tabletformulation under fed conditions reduced AUCs by approximately 18%,reduced C_(max) by approximately 22% and, based on median paireddifferences, delayed T_(max) by 0.5 hours compared with administrationunder fasted conditions. The mild food effect on atogepant PK is notconsidered clinically relevant.

Single doses of atogepant 60-mg IR formulation were safe andwell-tolerated by the healthy participants in this study whenadministered under both fed and fasted conditions. No clinicallymeaningful differences in safety or tolerability were observed followingadministration of a single dose of 60-mg atogepant IR formulation underfed conditions as compared with fasted conditions.

Overall 7 (35.0%) participants experienced treatment emergent AEs(TEAEs). Of these, 3 (15%) participants had 4 TEAEs that were consideredrelated to study intervention. The most frequently reported TEAEs werearthralgia and back pain (2 participants each, 10.0%). Of the 7participants who reported TEAEs, 6 experienced TEAEs that wereconsidered mild in severity and 1 participant experienced TEAEs ofincreased alanine aminotransferase and increased aspartateaminotransferase during follow-up that were considered moderate inseverity, documented as adverse events of special interest, andconsidered not related to study intervention. There were no deaths orsevere or serious TEAEs reported. No participants experienced TEAEs thatled to study discontinuation. All TEAEs were recovered/resolved by theFollow-Up Visit.

Changes from baseline in mean clinical laboratory, vital sign, andsafety 12-lead electrocardiogram (ECG) parameters were not clinicallymeaningful. Overall, 8 participants had potentially clinicallysignificant laboratory values at end of dosing (EOD), and noparticipants had liver function test results that met criteria for apotential Hy's Law case. No participants had vital sign or 12-lead ECGresults that met potentially clinically significant criteria during thestudy.

EXAMPLE 10

An open-label, single-center, multiple-dose 2-cohort, phase 1 trial wascarried out to assess the potential of a PK DDI between atogepant andtopiramate in healthy adult participants. Eligible participants wereenrolled either in cohort 1 to evaluate the effect of topiramate 100 mgtwice daily on the PK of atogepant 650 mg once daily or in cohort 2 toevaluate the effect of atogepant 60 mg once daily on the PK oftopiramate 100 mg twice daily. Participants in cohort 1 receivedatogepant alone on days 1-7 and atogepant plus topiramate on days 8-17.Participants in cohort 2 received topiramate alone on days 1-10 andtopiramate plus atogepant on days 11-17. The study design is set forthin FIG. 13 .

The duration of the study was 25 days (±2 days), which included day −1through the follow-up visit and excluded the screening period. Thescreening period was up to 21 days before day 1 and the interventionperiod was a total of 19 days, at which point the end of dosing visitwas conducted. Cerebrospinal fluid (CSF) samples for measurement ofatogepant concentration were collected via lumbar puncture in a subsetof consenting participants in cohort 1. CSF samples were collected oncefrom individual participants in the CSF collection subset at 2 or 6hours after the morning dose on day 6 for cohort 1. Clinical laboratorytests were performed at the follow-up visit, which was conducted on day24 (7 [±2] days after the last dose of study medication.

Eligible participants were healthy adults aged 18 to 45 years who werenonsmokers and had a body mass index between ≥18 and ≤30 kg/m2 and asitting pulse rate between ≥45 and ≤100 beats per minute. Participantswere excluded if they had clinically significant abnormalelectrocardiogram (ECG) results or QT prolongation (QTcF ≥450 msec formales, ≥470 for females), or any clinical condition or previous surgerythat may affect the absorption, distribution, biotransformation, orexcretion of atogepant or topiramate.

The primary endpoints were area under the plasma concentration-timecurve during dosing interval at steady state (AUC_(0-tau,ss)) andmaximum plasma drug concentration at steady state (C_(max,ss)) ofatogepant and topiramate when coadministered and when administeredalone. Additional PK parameters included time of maximum plasma drugconcentration at steady state (T_(max,ss)), average plasma drugconcentration at steady state (C_(avg,ss)), and minimum plasma drugconcentration at steady state (C_(min,ss)) of topiramate and atogepantwhen coadministered and when administered alone. Safety and tolerabilityof atogepant, topiramate, and their combination were monitoredthroughout the study by clinical assessment of adverse events (AEs),measurement of vital signs, evaluation of 12-lead ECGs, and clinicallaboratory tests (hematology, clinical chemistry, coagulation, andurinalysis) at specified time points.

The safety population included 28 participants in cohort 1 (28 receivedatogepant alone and 26 received atogepant plus topiramate; 24participants were included in the CSF collection subset) and 25participants in cohort 2 (25 received topiramate alone and 24 receivedtopiramate plus atogepant). The PK analysis population for atogepantalone and atogepant plus topiramate included 25 and 21 participants,respectively. The PK analysis populations for topiramate alone andtopiramate plus atogepant included 24 and 22 participants, respectively.A total of 21 participants in cohort 1 and 22 participants in cohort 2completed the trial. Ten participants discontinued the trial: 8participants due to AEs, 1 participant due to noncompliance with studydrug, and 1 participant due to other reasons (noncompliance with studyinvestigators). Baseline demographics were similar between the 2cohorts, as shown in Table 16.

TABLE 16 Baseline Demographics Cohort 1 Cohort 2 n = 28 n = 25 Age, mean(SD), years 33.3 (6.2) 33.6 (7.1) Male, n (%) 20 (71.4) 20 (80.0)Female, n (%) 8 (28.6) 5 (20.0) Race, n (%) White 11 (39.3) 7 (28.0)Black or African 15 (53.6) 16 (64.0) American BMI, mean (SD), kg/m² 26.9(2.3) 25.3 (3.0) Abbreviations: BMI, body mass index; SD, standarddeviation.

The mean (standard deviation [SD]) steady state plasma concentrations ofatogepant following administration alone and in combination withtopiramate are shown in FIG. 14 . These data demonstrate marginallylower atogepant plasma concentrations when atogepant was coadministeredwith topiramate compared with administration of atogepant alone. Table17 summarizes the PK parameters of atogepant alone and in combinationwith topiramate. Coadministration of atogepant and topiramate reducedatogepant C_(max,ss) compared with atogepant administered alone, whilethere was no change in the median T_(max,ss).

TABLE 17 Mean (±SD) PK parameters of atogepant alone (day 7) and incombination with topiramate (day 17) Atogepant 60 mg QD + AtogepantTopiramate 60 mg QD 100 mg BID PK Parameter n = 25 n = 21 T_(max, ss)(h) 2.0 (1-4)^(a) 2.0 (1-3)^(a) C_(max, ss) (ng/mL) 626.1 (376.9) 491.4(263.0) AUC_(0-tau, ss) (h · ng/mL) 3015.4 (1477.0) 2298.7 (1200.8)C_(min, ss) (ng/mL) 10.2 (13.1) 6.3 (4.9) C_(avg, ss) (ng/mL) 125.6(61.5) 95.8 (50.0) ^(a)Median (min-max) Abbreviations: AUC_(0-tau, ss),area under the plasma concentration vs time curve during dosing intervalat steady state; BID, twice daily; C_(avg, ss), average plasma drugconcentration at steady state; C_(max, ss), maximum plasma drugconcentration at steady state; C_(min, ss), minimum plasma drugconcentration at steady state; PK, pharmacokinetic; QD, once daily; SD,standard deviation; T_(max, ss), time of maximum plasma drugconcentration at steady state.

The analysis of GMRs showed that atogepant AUC_(0-tau,ss) and C_(max,ss)were reduced by 25% and 24%, respectively, when atogepant wascoadministered with topiramate, as shown in Table 18. The GMR and lower90% CI for both AUC_(0-tau,ss) and C_(max,ss) were below 0.80,suggesting a statistically significant reduction of atogepant exposurewhen coadministered with topiramate.

TABLE 18 Statistical analysis of PK parameters: comparison of plasmaatogepant alone and coadministered with topiramate Atogepant Atogepantand GMRs Atogepant Alone Topiramate (90% CI) PK Parameter Geometric LSMGeometric LSM (Combination/Alone) AUC_(0-tau, ss) (h · ng/mL) 2718.22026.4 0.75 (0.69, 0.81) C_(max, ss) (ng/mL) 535.2 405.8 0.76 (0.68,0.85) Abbreviations: AUC_(0-tau, ss), area under the plasmaconcentration vs time curve during dosing interval at steady state;C_(max, ss), maximum plasma drug concentration at steady state; CI,confidence interval; GMR, geometric mean ratio; LSM, least-square mean;PK, pharmacokinetic.

The mean (SD) steady state plasma concentrations of topiramate followingadministration alone and in combination with atogepant are shown in FIG.15 . Topiramate plasma concentrations were marginally lower whencoadministered with atogepant compared with topiramate alone. TopiramatePK parameters are summarized in Table 19. Overall, topiramate PKparameters were generally similar with and without coadministration ofatogepant; however, the median T_(max,ss) of topiramate was delayed by0.5 h when coadministered with atogepant. The analysis of GMRs showedthat topiramate AUC_(0-tau,ss) and C_(max,ss) were reduced by 5% and 6%,respectively, with atogepant coadministration, as shown in Table 20. TheGMRs and their 90% CIs for the C_(max) and AUC values were containedwithin the range 0.80 and 1.25, indicating no DDI.

TABLE 19 Mean (±SD) PK parameters of topiramate alone (day 10) and whencoadministered with atogepant (day 17) Topiramate 100 mg BID +Topiramate Atogepant 100 mg BID 60 mg QD PK Parameter n = 24 n = 22T_(max, ss) (h) 1.5 (0-4)^(a) 2.0 (0-4)^(a) C_(max, ss) (μg/mL) 7.7(1.6) 7.3 (1.8) AUC_(0-tau, ss) (h · μg/mL) 76.5 (15.7) 72.6 (16.9)C_(min, ss) (μg/mL) 5.2 (1.2) 4.7 (1.4) C_(avg, ss) (μg/mL) 6.4 (1.3)6.0 (1.4) ^(a)Median (min-max)AUC0-tau,ss, area under the plasma concentration vs time curve duringdosing interval at steady state; BID, twice daily; Cavg,ss, averageplasma drug concentration at steady state; Cmax,ss, maximum plasma drugconcentration at steady state; Cmin,ss, minimum plasma drugconcentration at steady state; PK, pharmacokinetic; QD, once daily; SD,standard deviation; Tmax,ss, time of maximum plasma concentration atsteady state.

TABLE 20 Statistical Analysis of PK Parameters: Comparison of PlasmaTopiramate Alone and Coadministered with Atogepant Topiramate TopiramateGMRs Atogepant PK Alone and Atogepant (90% CI) Parameter Geometric LSMGeometric LSM (Combination/Alone) AUC_(0-tau, ss) (h · μg/mL) 74.4 70.30.95 (0.88, 1.01) C_(max, ss) (μg/mL) 7.5 7.0 0.94 (0.87, 1.01)

AUC_(0-tau,ss), area under the plasma concentration vs time curve duringdosing interval at steady state; CI, confidence interval; C_(max,ss),maximum plasma drug concentration at steady state; GMR, geometric meanratio; LSM, least-square mean; PK, pharmacokinetic.

Topiramate AUC_(0-tau,ss) and C_(max,ss) were similar uponcoadministration with atogepant as compared to topiramate alone, whereasthe AUC_(0-tau,ss) and C_(max,ss) of atogepant decreased by 25% and 24%,respectively, due to mild induction of CYP3A4 by topiramate. However,these changes are expected to have minimal clinical significance andsuggest no dose adjustment is necessary with coadministration ofatogepant and mild CYP3A4 inducers.

For cohort 1 participants, the mean (SD) duration of exposure was 7.9(0.42) days with atogepant alone, 8.8 (2.79) days of atogepant andtopiramate coadministration, and 15.1 (3.62) days overall. For cohort 2participants, the mean (SD) duration of exposure was 10.0 (0.20) dayswith topiramate alone, 6.7 (1.23) days of topiramate and atogepantcoadministration, and 16.4 (1.96) days overall. A total of 24participants (85.7%) in cohort 1 and 19 participants (76.0%) in cohort 2reported at least 1 treatment-emergent adverse event (TEAE). TEAEs inthe safety population are summarized in Table 6.

TABLE 6 Overall Summary of TEAEs (Safety Population) Cohort 1 Cohort 2Atogepant Atogepant + Topiramate Topiramate + Event, Alone TopiramateAlone Atogepant n (%) n = 28 n = 26 n = 25 n = 24 TEAEs 20 (71.4) 17(65.4) 16 (64.0) 13 (54.2) Treatment-related 11 (39.3) 14 (53.8) 13(52.0) 10 (41.7) TEAEs Deaths 0 (0) 0 (0) 0 (0) 0 (0) TESAEs 0 (0) 0 (0)0 (0) 0 (0) Treatment-related 0 (0) 0 (0) 0 (0) 0 (0) TESAEs TEAEsleading to 5 (17.9)^(a) 1 (3.8)^(a) 2 (8.0) 1 (4-2) discontinuation^(a)One participant reported a TEAE during atogepant administration anda TEAE during combination of atogepant and topiramate.

The most commonly reported adverse events were nausea and constipation.Nausea was reported by 6 participants receiving atogepant alone and by 2participants during atogepant and topiramate coadministration incohort 1. In cohort 2, nausea was reported by 3 participants receivingtopiramate alone and by 0 participants during topiramate and atogepantcoadministration. Constipation was reported by 3 participants receivingatogepant alone and by 0 participants during atogepant and topiramatecoadministration in cohort 1. In cohort 2, constipation was reported by2 participants receiving topiramate alone and by 2 participants duringtopiramate and atogepant coadministration.

Five participants experienced a TEAE during administration of atogepantalone that led to discontinuation. One participant who reportedincreased aspartate aminotransferase/alanine aminotransferase and oneparticipant who reported confusional state and insomnia discontinuedduring the atogepant alone study period. Two participants whoexperienced a TEAE during administration of atogepant alone (nausea andprocedural pain [post lumbar puncture neck pain]; and post lumbarpuncture syndrome) were able to complete atogepant dosing anddiscontinued the trial during the atogepant and topiramatecoadministration period. One additional participant experienced a TEAEof nausea during administration of atogepant alone and a TEAE ofmuscular weakness during the atogepant and topiramate coadministrationperiod; this participant discontinued during the coadministrationperiod.

The incidence of treatment-related TEAEs was similar across treatmentinterventions and no serious AEs or deaths occurred during the trial.Clinical laboratory, vital sign, and ECG assessments revealed noclinically relevant findings and no participants met the criteria for apotential Hy's law case (aminotransferase >3 times the upper limit ofnormal [ULN], total bilirubin ≥2 times the ULN, and alkaline phosphatase<2 times ULN).

Administration of atogepant and topiramate, either alone or incombination, is safe and well tolerated in healthy adults.

1. A method for the preventive treatment of episodic migraine in apatient undergoing concurrent treatment with a strong CYP3A4 inhibitor,the method comprising administering 10 mg atogepant once daily.
 2. Themethod according to claim 1, wherein coadministration of atogepant andthe strong CYP3A4 inhibitor results in an increase in atogepant C_(max)of less than 2.15-fold relative to administration of atogepant alone. 3.The method according to claim 1, wherein coadministration of atogepantand the strong CYP3A4 inhibitor results in an increase in atogepant AUCof about 5.5-fold relative to administration of atogepant alone.
 4. Themethod according to claim 1, wherein the CYP3A4 inhibitor is selectedfrom the group consisting of ketoconazole, itraconazole, orclarithromycin.
 5. The method according to claim 1, wherein the CYP3A4inhibitor is itraconazole. 6-11. (canceled)
 12. A method for thepreventive treatment of episodic migraine in a patient undergoingtreatment with a strong or moderate CYP3A4 inducer, the methodcomprising administering 30 mg or 60 mg atogepant.
 13. The methodaccording to claim 12, wherein the CYP3A4 inducer is selected from thegroup consisting of rifampin, carbamazepine, phenytoin, St. John's wort,efavirenz, or etravirine.
 14. The method according to claim 12, whereinatogepant is administered when the CYP3A4 inducer has reached a steadystate.
 15. The method according to claim 14, wherein the AUC ofatogepant is decreased by about 60% when atogepant is coadministeredwith the moderate or strong CYP3A4 inducer, relative to administrationof atogepant alone.
 16. A method for the preventive treatment ofepisodic migraine in a patient undergoing treatment with an OATPinhibitor, the method comprising administering 10 mg or 30 mg atogepantonce daily.
 17. The method according to claim 16, whereincoadministration of atogepant with the OATP inhibitor results in anincrease in atogepant C_(max) of about 2.2-fold relative toadministration of atogepant alone. 18-21. (canceled)